Outpatient Management of Stable Acute Pulmonary Embolism

The American Journal of Medicine (2007) Vol 120 (10B), S18 –S25 Outpatient Management of Stable Acute Pulmonary Embolism: Proposed Accelerated Pathway for Risk Stratification Amjad AlMahameed, MD, MPH,a and Teresa L Carman, MDb a Division of Cardiology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA; and bSection of Vascular Medicine, Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio, USA ABSTRACT Pulmonary embolism (PE) is a major health problem and a cause of worldwide morbidity and mortality The current standard therapy for acute PE encourages admitting patients to the hospital for administration of parenteral anticoagulation therapy as a bridge to oral vitamin K antagonists Prognostic models that identify patients with stable (nonmassive) acute PE (SPE) who are at low risk for adverse outcome have recently been reported Based on these risk stratification models, hospital-based therapy is warranted for patients with PE who meet the criteria associated with a high risk for adverse outcome However, a growing body of evidence suggests the feasibility of partial outpatient management and accelerated hospital discharge (AHD) in a subset of patients with SPE Prospective validation of these risk stratification models for predicting patient suitability for AHD is needed © 2007 Elsevier Inc All rights reserved KEYWORDS: Anticoagulation; Pharmacotherapy; Pulmonary embolism; Risk stratification; Treatment; Venous thromboembolism Deep vein thrombosis (DVT) and pulmonary embolism (PE) are manifestations of the same disease process referred to collectively as venous thromboembolism (VTE) Despite increased awareness and wider employment of reliable thromboprophylactic strategies, the incidence of first-time symptomatic VTE remains high at 71 to 117 cases per 110,000 population.1 Up to 33% of all patients with symptomatic DVT manifest PE at the time of presentation Nearly 50% of individuals with proximal (i.e., suprapopliteal or above-the-knee) DVT have radiographic evidence of a coexistent PE,2 and most fatal emboli are likely to arise from this region.3 Although the risk of embolization may be lower with untreated distal (i.e., calf vein or infrapopliteal) DVT, proximal propa- Please see the Conflict of Interest section at the end of this article Requests for reprints should be addressed to Amjad AlMahameed, MD, MPH, Division of Cardiology, Beth Israel Deaconess Medical Center, Harvard Medical School, Deaconess Road (Baker 4), Boston, Massachusetts 02115 E-mail address: aalmaham@bidmc.harvard.edu 0002-9343/$ -see front matter © 2007 Elsevier Inc All rights reserved doi:10.1016/j.amjmed.2007.08.010 gation is seen in as many as 25% of such thrombi, further increasing the risk for PE Patients with a history of PE are almost times more likely to die of recurrent VTE in the following year than are patients who are treated for DVT alone.4 It is estimated that about 237,000 nonfatal and 294,000 fatal cases of PE occur in the United States each year.5 A total of 34% of VTE-related deaths were due to sudden massive PE and 59% followed undiagnosed PE PE presents with a wide clinical spectrum and largely nonspecific symptoms; therefore, timely diagnosis requires a high degree of clinical suspicion Studies suggest that 55% to 94% of PEs in medical patients are not diagnosed until autopsy.6,7 These numbers most likely have been underestimated because autopsies are not routinely conducted in contemporary practice It has been suggested that up to 27% to 68% of fatal PE cases are potentially preventable.8 Thus, rigorously screening for VTE risk factors and implementing effective thromboprophylaxis, along with prompt diagnosis and early therapy of suspected cases, is warranted AlMahameed and Carman Risk Stratification in Outpatient Management of Stable Acute PE RISK STRATIFICATION Acute PE generally can be classified as either massive PE or nonmassive SPE.9 Patients with massive acute PE have a uniformly poor prognosis and the first few hours is the critical period when the majority of deaths occur It is during this narrow window when prompt diagnosis and rigorous treatment strategies can save lives.10 Hemodynamic instability with systemic hypotension, cardiogenic shock, severe dyspnea, or respiratory failure at the time of presentation defines a physiologically massive PE Massive acute PE is associated with increased risk for early mortality.9,10 According to reports from the International Cooperative Pulmonary Embolism Registry (ICOPER), the incidence of mortality at months in patients with hemodynamic instability was 58% compared with 15% in patients who were hemodynamically stable.11 Radiographically large PE has been defined as angiographic obstruction of Ն50% or Ն2 lobar arteries.10,12 SPE, on the other hand, is not associated with hemodynamic instability or respiratory failure and has a much lower risk for mortality (Ͻ5%).9 These patients may be asymptomatic, or may present with mild or moderate dyspnea, cough, pleuritic chest pain, or other clinical complaints The mortality in SPE is significantly higher (26%) if these patients experience recurrent PE.9 SPE remains a serious condition and clinicians should focus on preventing recurrent emboli, particularly early after the initial PE, and not be deceived into inaction by the low initial mortality rate Using clinical factors alone, many patients presenting with acute PE can be classified as either unstable, thus requiring intensive inhospital therapy, or stable and at low risk for adverse events and potentially amenable to accelerated hospital discharge (AHD) Table 113–26 outlines important predictors of adverse outcomes in patients with acute PE The Geneva Risk Score (GRS) is a clinical scoring system (Table 216) that has undergone both internal and external validation The GRS was developed using multivariate analysis of clinical factors present at the time of admission in 296 consecutive patients with confirmed PE.16 Independent predictors of adverse outcome were history of cancer, congestive heart failure, previous DVT, systolic blood pressure Ͻ100 mm Hg, arterial oxygen pressure Ͻ8 kPa, and acute DVT on ultrasonography at the time of presentation Risk scores were assigned to each variable and cross-validated (Table 2) During the 3-month follow-up, 2.2% (4 of 180) of low-risk patients (a score Յ2) experienced an adverse clinical outcome, including death, recurrent thromboembolism, or bleeding, compared with 26% in high-risk patients (score of Ն3).16 A recent retrospective study externally validated the GRS for identifying patients with acute PE who were at low risk for an adverse clinical outcome.15 A second retrospective study derived a prediction rule for PE outcomes by randomly selecting 10,354 of 15,531 individuals discharged from 186 US hospitals with a diagnosis of PE.13 In all, 11 demographic, comorbid conditions S19 Table Predictor variables of adverse outcomes in patients with acute pulmonary embolism ● Clinical parameters13–16 —Age Ͼ70 yr at onset —Heart failure —Cancer —Previous DVT —Chronic lung disease —Chronic renal disease —Cerebrovascular disease (TIA or stroke) —Systemic arterial hypotension (SBP Ͻ100 mm Hg) —Hypoxemia (O2 saturation Ͻ90% with/without O2 supplementation) —Tachycardia (HR Ն 110 beats/min) ● Parameters for right ventricular dysfunction17–23 —Electrocardiogram X T-wave inversion in leads V1–V4 X New right bundle branch block X S1Q3T3 —Echocardiographic X RV hypokinesis X Persistent pulmonary hypertension X Patent foramen ovale X Free-floating right-heart thrombus —CT scan X RV/LV ratio Ͼ0.9 on the reconstructed CT 4-chamber view identifies patients at increased risk for early death ● Cardiospecific biomarkers24–26 —Pro-BNP X Ͻ50 pg/mL identifies 95% of patients with a benign clinical course —Troponin (positive troponin I or T in the absence of primary cardiac ischemia) X Indicates RV microinfarction X The higher the value, the worse the prognosis BNP ϭ brain natriuretic peptide; CT ϭ computed tomography; DVT ϭ deep vein thrombosis; HR ϭ heart rate; RV ϭ right ventricular; RV/LV ϭ right ventricular/left ventricular; SBP ϭ systolic blood pressure; TIA ϭ transient ischemic attack Adapted from Am J Respir Crit Care Med,13 Arch Intern Med,14 Thromb Haemost,15,16 Circulation,17,19,21,22,24,26 Ann Intern Med,18 Arch Intern Med,20 Radiology,23 and Eur Heart J.25 Table The Geneva Risk Score Variable Point Score Cancer Heart failure Systolic blood pressure Ͻ100 mm Hg Prior DVT Hypoxemia DVT on ultrasound ϩ2 ϩ1 ϩ2 ϩ1 ϩ1 ϩ1 DVT ϭ deep vein thrombosis Adapted from Thromb Haemost.16 and physical examination findings were validated as predictors of 30-day all-cause mortality and other severe nonfatal complications, such as cardiogenic shock and cardiopulmonary arrest during hospitalization (Table 1, see clinical S20 The American Journal of Medicine, Vol 120 (10B), October 2007 Figure An integrated approach to the risk stratification of patients with acute pulmonary embolism (PE) BNP ϭ brain natriuretic peptide; CT ϭ computed tomography; RV ϭ right ventricular; ϭ increase; ϭ decrease (Reprinted with permission from Circulation.38 © 2006 American Heart Association, Inc.) parameters) More than 20% of patients enrolled in the study did not present with any of these variables, and thus were deemed to be at low risk The incidences of 30-day mortality and serious adverse outcomes in the low-risk group were low (0% to 1.6% and Ͻ1.1%, respectively) compared with the high-risk group (4.0% to 11.4% and 1.9% to 2.1%, respectively) Despite the valuable information provided by the initial clinical assessment, there is a subgroup of patients with PE who may appear well but decompensate shortly thereafter owing to right ventricular compromise In this setting assessment of right ventricular function and the use of biomarkers may be helpful to further risk stratify these patients Right ventricular dysfunction (RVD) can be evaluated on the basis of physical examination, electrocardiography, and chest computed tomography (CT).19 Moderate or severe RVD in normotensive patients is an indicator of physiologically large emboli and is associated with worse prognosis,27,28 including up to 10% mortality.29 Although echocardiography may be useful for risk stratification, it should not be used alone to establish the diagnosis of PE.12,28,30 Tests for cardiospecific biomarkers, in particular cardiac troponins (cTnT and cTnI) and brain natriuretic peptides (BNPs) may be used for objective risk stratification of patients with acute PE (Table 1).19,24 –26,29 These tests are readily available, inexpensive, reproducible, and accurate Patients with elevated BNP and troponin levels are more likely to have RVD26,29,31–36 and benefit from closer observation Low BNPs and troponin levels have a high negative predictive value for inhospital death and other adverse outcomes,26,29,31,34 including the need for pressor support, me- chanical ventilation, intensive care transfer, and prolonged length of stay These patients may be candidates for AHD.26 Biomarkers should be evaluated both at presentation and after 12 hours because a delayed release (particularly troponin) may be observed after to 12 hours.29,37 In addition to formal clinical assessment, our practice frequently incorporates the use of biomarkers and measures of RV function (such as echocardiography and CT scan) to further risk stratify patients Recent reports have called for incorporating cardiac biomarkers into PE management decision algorithms (Figure 1),19,24,25,29,38 although such a strategy has not been adopted by formal consensus guidelines.29 GUIDELINES AND CURRENT STANDARDS FOR TREATMENT OF PULMONARY EMBOLISM The American College of Chest Physicians (ACCP) has developed guidelines for initial treatment of acute PE (Table 3).4,39 Although the ACCP recommends considering systemic thrombolysis (grade 2B; see Table for explanation of grades) or surgical embolectomy (grade 2C) for patients presenting with massive PE,4,29,40 the use of these therapies in patients with SPE is controversial.40 Surgical embolectomy carries operative mortality ranging from 20% to 50%, and the incidence of major bleeding complications with thrombolytic therapy is twice that seen in patients treated with heparin alone.40 For nearly half a century, intravenous infusion of unfractionated heparin (UFH) followed by oral administration of warfarin has been the cornerstone of treatment for acute AlMahameed and Carman Risk Stratification in Outpatient Management of Stable Acute PE S21 Table American College of Chest Physicians (ACCP) recommendations for the initial treatment of patients with acute pulmonary embolism (PE) Grade/Level of Evidence* Treatment Diagnosis/Symptoms Recommendation Intravenous UFH or LMWH Objectively confirmed nonmassive PE Short-term treatment with SC LMWH or IV UFH Treatment with anticoagulants while awaiting the outcome of diagnostic tests LMWH over UFH Initial treatment with LMWH or UFH for Ն5 days Recommend against systemic thrombolytic therapy 1A Consider thrombolytic therapy Recommend against use of mechanical approaches Consider use of mechanical approaches 2B 1C High clinical suspicion of PE Acute nonmassive PE Acute nonmassive PE Systemically and locally administered thrombolytic drugs Most patients with PE Acute massive PE Most patients with PE Catheter extraction or Patients with acute massive PE who are fragmentation unable to receive thrombolytic therapy Pulmonary embolectomy Most patients with PE Recommend against pulmonary embolectomy Patients with acute massive PE who are Consider pulmonary embolectomy unable to receive thrombolytic therapy Vena caval interruption In patients with PE with a contraindication Placement of an inferior vena caval filter for, or a complication of anticoagulant treatment, as well as in those with recurrent thromboembolism despite adequate anticoagulation 1Cϩ 1A 1C 1A 2C 1C 2C 2C IV ϭ intravenous; LMWH ϭ low-molecular-weight heparin; RCT ϭ randomized clinical trial; SC ϭ subcutaneous; UFH ϭ unfractionated heparin *Explanation of grades of recommendation and levels of evidence: ● Grade 1: Strong recommendation; certain that benefits do, or not, outweigh risks, burden, and costs ● Grade 2: Weaker recommendation; less certain of the magnitude of benefits and the impact of risks, burden, and costs ● Level of evidence A: RCTs with consistent results ● Level of evidence B: RCTs with inconsistent results or with major methodologic weaknesses ● Level of evidence C: Observational studies or from a generalization from group of patients included in RCTs to a different, but somewhat similar, group of patients who did not participate in those trials If generalizations are secure or observational study data are compelling, grade Cϩ can be designated Adapted from Chest.4,39 VTE.41 The full anticoagulant effects of warfarin are seen only after to days of administration Thus, in patients with acute VTE, warfarin must always be administered in conjunction with a rapidly acting parenteral anticoagulant UFH has pharmacologically limiting properties, including a poor dose-response curve and a relatively narrow therapeutic window, requiring close monitoring and frequent dose adjustments These issues make its use in the outpatient setting somewhat difficult.42 In addition, in some patients, UFH may cause immune-mediated thrombocytopenia and thrombosis.3 The use of newer anticoagulants with better bioavailability and more consistent therapeutic response along with recent advances in risk stratification have led to improved treatment outcomes in patients with VTE.19 Three lowmolecular-weight heparins (LMWHs), dalteparin, tinzaparin, and enoxaparin, are approved by the US Food and Drug Administration (FDA) for treatment of acute symptomatic DVT with or without PE in hospitalized patients Several reports have been published using LMWHs (including tin- zaparin, dalteparin, enoxaparin, and nadroparin) to treat acute PE outside the hospital (Table 4).43– 48 Fondaparinux is another anticoagulant that has been approved by the FDA specifically for outpatient treatment of PE in conjunction with warfarin when initial therapy is administered in the hospital.49 It is a synthetic pentasaccharide compound that selectively inhibits factor Xa through an antithrombin-mediated mechanism Its relatively long halflife (17 to 21 hours in individuals with normal renal function) allows for once-daily subcutaneous injection using a simplified weight-based dosing The risk of heparin-induced thrombocytopenia with fondaparinux is negligible.50 The efficacy and safety of once-daily subcutaneous fondaparinux for the initial treatment of PE were recently prospectively evaluated in comparison with continuous intravenous UFH in 2,213 subjects enrolled in the phase 3, randomized Mondial Assessment of Thromboembolism Treatment Initiated by Synthetic Pentasaccharide with Symptomatic Endpoints (MATISSE-PE) trial.51 The aim of MATISSE-PE was to compare the rates of VTE recurrence S22 Table Prospective studies evaluating outpatient anticoagulation therapy following acute pulmonary embolism (PE) Study Patient Group Wells et al., 1998 (Canada)43 ● n ϭ 194 ● Low risk* with DVT and/or PE treated as outpatients ● 34 patients had confirmed PE ● n ϭ 108 ● Patients with PE treated as outpatients‡ Kovacs et al., 1998 (Canada)44 Labas et al., 2001 (Slovakia)45 Treatment ● Dalteparin (100 U/kg bid or 200 U/kg qd) administered at home for Ն5 days ● Warfarin coadministration ● 3-mo follow-up ● Dalteparin (200 U/kg qd) administered at home for Ն5 days ● Warfarin coadministration ● 3-mo follow-up ● Enoxaparin (1 mg/kg bid) administered ● n ϭ 106 for Ն7 days ● Patients diagnosed with DVT ● Warfarin coadministration and/or PE ● 28 patients had confirmed PE ● Elastic compression stockings and recommended mobilization ● Nadroparin 171 U/kg administered for 5–10 days ● Warfarin coadministration for 6-12 mo ● Tinzaparin (175 U/kg qd) for Ն6 days ● Warfarin coadministration ● Tinzaparin (175 U/kg qd) for 5– days ● Warfarin coadministration for mo ● Clinical symptoms and repeat V/Q scan assessed at day to evaluate recurrent PE Key Results Recurrent VTE Major hemorrhage Minor hemorrhage Death Recurrent VTE Major hemorrhage Death 3.6% (7/194) Small no of patients 2.0% (4/194) with PE 5.1% (10/194) 7.2%† (14/194) 5.6% (6/108) 81 patients were managed 1.9% (2/108) exclusively as 3.7%§ (4/108) outpatients Death at –12 wk Recurrent VTE at 1-yr follow-up (0/90) (0/46) Recurrent PE Bleeding at mo Death at mo Significant adverse events# during the treatment phase Recurrent PE (new mismatched defects) at late follow-up (4 – 46 mo) Death after 1– mo Required hospitalization 2.3% (1/43) (0/43) (0/43) (0/93) 8.5% (5/59) Remarks ● Small no of patients with PE ● Limited details given regarding diagnostic criteria for PE or for outpatient treatment Small no of patients with PE Outcome data only available for treatment phase V/Q scans at late follow-up were only performed in 58% of patients 4%†† (4/100) 5% (5/100) DVT ϭ deep vein thrombosis; VTE ϭ venous thromboembolism; V/Q ϭ ventilation/perfusion *Patients were eligible for outpatient treatment if they had been objectively diagnosed with DVT, unless they had massive pulmonary embolism, high risk for major bleeding or an active bleed, phlegmasia, or were hospitalized for reasons that prevented discharge.43 † Causes of death included cancer (n ϭ 11), sepsis (n ϭ 1), myocardial infarction (n ϭ 1), and sudden death not attributed to PE (n ϭ 1) ‡ Patients were eligible for outpatient treatment if they had been objectively diagnosed with PE, and did not meet any of the following criteria: admitted to the hospital for another reason; experienced active bleeding or were at high risk for major bleeding, hemodynamic instability, or pain requiring narcotics; required oxygen therapy; were aged Ͻ18 years, or were at risk for poor adherence.44 § Deaths not attributed to bleeding complications or PE ʈ Based on risk score assessment described by Wicki et al., 2000.16 ¶ Patients were eligible for outpatient treatment if they had been objectively diagnosed with PE, and were not at the highest risk for major bleeding (intracerebral bleed within the last months, gastrointestinal bleed in the last month, or verified bleeding disorder) Patients with renal or liver failure, pregnancy, or gross hypertension were evaluated on an individual basis.47 # Significant adverse events included bleeding, thromboembolic complications, and death **Patients were excluded if PE was extensive, defined as Ͼ7 segments with reduced perfusion (representing Ͼ 40% of the total lung perfusion); had severe, concomitant lung disease such as COPD, pneumonia, and heart failure; had other reason for hospitalization (e.g., recent surgery, bleeding, or severe pain).48 †† Causes of death included cancer (n ϭ 11), renal insufficiency (n ϭ 1), cerebral bleeding (n ϭ 1), and massive pleural effusion/thoracocentesis (n ϭ 1) Adapted from Arch Intern Med,43 Thromb Haemost,44 Bratisl Lek Listy,45 J Thromb Haemost,46 Blood,47 and Med Sci Monit.48 The American Journal of Medicine, Vol 120 (10B), October 2007 Beer et al., ● n ϭ 43 2002 (Switzerland)46 ● Patients with symptomatic PE at low predicted riskʈ Rhodes et al., ● n ϭ 107 2005 (United ● Patients with confirmed PE Kingdom)47 treated as outpatients¶ Olsson et al., ● n ϭ 102 2006 (Sweden)48 ● Patients with symptomatic small or medium-sized PE quantified by V/Q scan** ● Patients had daily visits to outpatient office Outcomes AlMahameed and Carman Risk Stratification in Outpatient Management of Stable Acute PE during the 3-month follow-up period and major bleeding and death during the initial treatment period Fondaparinux was administered as a once-daily subcutaneous dose of 7.5 mg (adjusted to mg and 10 mg for patients weighing Ͻ50 kg and Ͼ100 kg, respectively) Only 42 (3.8%) of 1,103 patients who received fondaparinux had recurrent VTE events compared with 56 (5.0%) of 1,110 patients assigned to receive UFH, for an absolute difference of Ϫ1.2 percentage points in favor of fondaparinux (P ϭ NS) Major and nonmajor bleeding, thrombocytopenia, and mortality were similar in both groups during the entire period of the study The current ACCP recommendations for SPE involves admitting all patients to the hospital for administration of parenteral anticoagulation therapy, either UFH or LMWH, as a bridge to warfarin with a minimum of days of overlap until a therapeutic international normalized ratio (INR) Ͼ2.0 is achieved.4 Warfarin should be continued for a minimum of to 12 months Fondaparinux was not yet approved for treatment of DVT and PE when the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy developed treatment guidelines; therefore, this option was not included when the guidelines were released in 2004 BENEFITS OF OUTPATIENT TREATMENT There is growing evidence that AHD and partial outpatient therapy is feasible for patients with nonmassive SPE.44 – 48,51–57 Partial outpatient treatment of PE via an AHD program may be offered to patients deemed to be at low risk for mortality, recurrent PE, or major bleeding complications; who have a home environment with adequate support; and who are able to self-administer the medications (see Tables and for risk stratification criteria).53,54 In study, up to 83% of VTE patients qualified for outpatient treatment.43 Benefits of outpatient management include improved quality-of-life measures,58 increased physical activity and social functioning,58 reduced length of stay,58,59 and substantial cost savings.52,60,61 Pharmacoeconomic analyses of outpatient treatment for DVT reported cost reductions of 34% to 64%.52 Agnelli and colleagues52 reported Ͼ$2,400 in cost savings per patient when acute PE was treated on an outpatient basis However, despite these incentives, clinicians are rightfully disinclined to send home patients who might be at risk for an unfavorable outcome.16 Several studies have demonstrated successful outpatient therapy with LMWH as a bridge to warfarin for the treatment of acute SPE (Table 4).43– 48 In addition, 158 patients in the fondaparinux group of the MATISSE-PE trial were permitted early discharge and received fondaparinux partly on an outpatient basis51,59; of these patients had recurrent VTE, and none had major bleeding or died during initial treatment.59 In light of the current data and the consideration for AHD with partial outpatient therapy of acute PE, there is a need to accurately predict patient suitability for this type of therapy It is likely that identification of low-risk S23 patients with acute PE will facilitate less complex treatment and allow for earlier discharge without sacrificing efficacy or safety SUMMARY Acute PE has a wide clinical spectrum, ranging from asymptomatic patients to those presenting with sudden death The clinical course in patients who survive an initial thromboembolic episode can be complicated by recurrent nonfatal VTE, fatal PE, postthrombotic syndrome, and chronic thromboembolic pulmonary hypertension Early identification of high-risk patients with acute PE who are at increased risk for adverse outcomes remains a challenge in clinical practice A substantial subset of patients with stable PE may be amenable to outpatient treatment; however, appropriate risk stratification is necessary to identify these candidates Outpatient treatment in these patients can reduce hospital stay, improve patient quality of life, and decrease healthcare costs Further studies are needed to establish clear clinical pathways that prospectively use contemporary risk stratification criteria for AHD of patients presenting with acute SPE Treatment of acute PE with LMWH or fondaparinux administered in an outpatient setting for appropriately selected patients is at least as effective and safe as conventional inpatient treatment with UFH in preventing recurrent VTE, without increasing the risk for major bleeding when patients are closely monitored Phase clinical trials have shown fondaparinux to be an effective alternative to LMWHs and UFH for the outpatient treatment of DVT62; additionally, these trials have shown it to be efficacious in inpatient and partial outpatient treatment of PE.51 Fondaparinux currently is the only FDA-approved medication for partial outpatient treatment of SPE CONFLICT OF INTEREST These authors report the following conflicts of interest with the sponsor of this supplement article or products discussed in this article Teresa L Carman, MD, has served as a member of the Speakers’ Bureau for Bristol-Myers Squibb Company Amjad AlMahameed, MD, has served as a member of the Speakers’ Bureau for sanofi-aventis and GlaxoSmithKline References White RH The epidemiology of venous thromboembolism 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